An Investigation of Further Strategies to Optimize Early Treatment Gains in Brief Therapies for Insomnia.

OBJECTIVES: Identifying those who are most (and least) likely to benefit from a stepped-care approach to cognitive behavioral therapy for insomnia (CBT-I) increases access to insomnia therapies while minimizing resource consumption. The present study investigates non-targeted factors in a single-session of CBT-I that may act as barriers to early response and remission. METHODS: Participants (N = 303) received four sessions of CBT-I and completed measures of subjective insomnia severity, fatigue, sleep-related beliefs, treatment expectations, and sleep diaries. Subjective insomnia severity and sleep diaries were completed between each treatment session. Early response was defined as a 50% reduction in Insomnia Severity Index (ISI) scores and early remission was defined by < 10 on the ISI after the first session. RESULTS: A single-session of CBT-I significantly reduced subjective insomnia severity scores and diary total wake time. Logistic regression models indicated that lower baseline fatigue was associated with increased odds of early remission (B = -.05, p = .02), and lower subjective insomnia severity (B = -.13, p = .049). Only fatigue was a significant predictor of early treatment response (B = -.06, p = .003). CONCLUSIONS: Fatigue appeared to be an important construct that dictates early changes in perceived insomnia severity. Beliefs about the relationship between sleep and daytime performance may hinder perceived improvements in insomnia symptoms. Incorporating fatigue management strategies and psychoeducation about the relationship between sleep and fatigue may target non-early responders. Future research would benefit from further profiling potential early insomnia responders/remitters.

Examining whether Changes in Sleep Habits Predict Long-Term Sustainment of Treatment Gains in Individual Remitted from Insomnia after CBT-I.

OBJECTIVES: Providers of Cognitive-Behavioral Therapy for Insomnia (CBT-I) are often asked whether the behavioral recommendations (e.g., stimulus control, sleep restriction) must be adhered to ad infinitum. We examined whether changes in sleep habits/behaviors are a life sentence, or whether patients who remit can relax their adherence while maintaining their treatment gains at 1-year follow-up (FU). METHODS: Participants (N = 179) completed 2 weeks of sleep diaries and measures of insomnia severity and safety behaviors at baseline and following four sessions of CBT-I. Of the 137 patients that achieved remission, 77 completed these measures at 1-year FU. RESULTS: Improvements in insomnia severity and total wake time (TWT) at post-treatment were maintained at FU (ps ≥ .52). Similarly, reductions in safety behaviors were maintained at FU (p - 1.00), whereas lingering in bed reduced during treatment (p < .001) but increased at FU (p < .001). Changes in sleep habits after treatment did not predict insomnia severity at FU. However, increases in time in bed positively predicted TWT at FU (p = .001). CONCLUSIONS: Those who remit after CBT-I may generally relax their adherence to behavioral recommendations without significantly impacting their perceived insomnia symptoms 1 year after treatment despite some increases in TWT. Results increase our confidence in CBT-I as a brief and durable intervention.

Cognitive-behavioral, behavioural and mindfulness-based therapies for insomnia in menopause.

OBJECTIVES: Insomnia is frequently reported by women during menopause due to physiological changes and environmental factors and is associated with negative daytime sequelae. Due to medication side effects and patient preferences, there is increased interest in the use of psychological treatments for menopausal insomnia. The primary objective of this review is to review the efficacy of cognitive-behavioral, behavioral, and mindfulness-based (CBBMB) therapies in treating insomnia in peri- and post-menopausal women. The secondary objective is to review the effect of CBBMB therapies on relevant secondary outcomes to gain a comprehensive understanding of their impacts. METHODS: We conducted a narrative review of the literature. A search of PubMed and Google Scholar was conducted between January 2020 and March 2021. RESULTS: Cognitive-behavioral therapy (CBT) for insomnia is efficacious, with corollary improvements in mood, functional outcomes and potential mechanistic factors (e.g., unhelpful beliefs). Sleep restriction therapy is also efficacious, with somewhat poorer effects on secondary outcomes relative to CBT. Mindfulness meditation and relaxation for insomnia demonstrated promise, but its long-term effects remain unknown. CONCLUSIONS: Research with more diverse samples and head-to-head comparisons is needed. Dissemination of CBBMBs for insomnia in clinics where menopausal women seek care is an important next step.

Peripheral inflammatory biomarkers define biotypes of bipolar depression.

We identified biologically relevant moderators of response to tumor necrosis factor (TNF)-α inhibitor, infliximab, among 60 individuals with bipolar depression. Data were derived from a 12-week, randomized, placebo-controlled clinical trial secondarily evaluating the efficacy of infliximab on a measure of anhedonia (i.e., Snaith-Hamilton Pleasure Scale). Three inflammatory biotypes were derived from peripheral cytokine measurements using an iterative, machine learning-based approach. Infliximab-randomized participants classified as biotype 3 exhibited lower baseline concentrations of pro- and anti-inflammatory cytokines and soluble TNF receptor-1 and reported greater pro-hedonic improvements, relative to those classified as biotype 1 or 2. Pretreatment biotypes also moderated changes in neuroinflammatory substrates relevant to infliximab's hypothesized mechanism of action. Neuronal origin-enriched extracellular vesicle (NEV) protein concentrations were reduced to two factors using principal axis factoring: phosphorylated nuclear factorκB (p-NFκB), Fas-associated death domain (p-FADD), and IκB kinase (p-IKKα/ß) and TNF receptor-1 (TNFR1) comprised factor "NEV1," whereas phosphorylated insulin receptor substrate-1 (p-IRS1), p38 mitogen-activated protein kinase (p-p38), and c-Jun N-terminal kinase (p-JNK) constituted "NEV2". Among infliximab-randomized subjects classified as biotype 3, NEV1 scores were decreased at weeks 2 and 6 and increased at week 12, relative to baseline, and NEV2 scores increased over time. Decreases in NEV1 scores and increases in NEV2 scores were associated with greater reductions in anhedonic symptoms in our classification and regression tree model (r2 = 0.22, RMSE = 0.08). Our findings provide preliminary evidence supporting the hypothesis that the pro-hedonic effects of infliximab require modulation of multiple TNF-α signaling pathways, including NF-κB, IRS1, and MAPK.

Characterizing the gut microbiota in adults with bipolar disorder: a pilot study.

Background: Convergent evidence implicates gut microbiota in human health and disease. Hitherto, relatively few studies have evaluated the gut microbiota profile in individuals with bipolar disorder (BD) relative to healthy controls (HC). Methods: Fecal samples were collected from subjects (aged 18-65) meeting DSM-5-defined criteria for BD and age- and sex-matched HC without current or past history of mental or major medical disorders. Samples were sequenced using Illumina sequencing and association of specific taxa and co-occurrence of taxa with sample groups including the effect of diet was assessed using cluster analysis and analysis of communities of microorganisms (ANCOM). Nutritional composition was evaluated using the Dietary Questionnaire for Epidemiological Studies (DQES v2) Food Frequency Questionnaire. Results: Forty-six subjects were enrolled (n=23 BD, n=23 HC). Cluster analyses did not identify any significant differences between BD and HC (p=0.38). Lower microbiota diversity was observed among BD subjects relative to HC (p=0.04). A greater abundance of a Clostridiaceae OTU was observed among BD subjects when compared to HC and of Collinsella among BD-II subjects relative to BD-I. Cluster analysis revealed that neither diagnosis (p=0.38) nor diet (p=0.43) had a significant effect on overall gut microbiota composition. Limitations: This study has a small sample size and insufficient control for some potential moderating factors (e.g. psychotropic medication and smoking). Conclusion: This study suggests that individuals with BD may have a distinct gut microbiota profile compared to healthy controls, with a greater abundance of Clostridiaceae and Collinsella. These findings need to be replicated in future studies with larger sample sizes.

Efficacy of adjunctive infliximab vs. placebo in the treatment of anhedonia in bipolar I/II depression.

We investigated the efficacy of tumour necrosis factor (TNF)-α antagonist infliximab on a measure of anhedonia amongst individuals with bipolar I/II depression (ClinicalTrials.gov identifier NCT02363738). Adults (ages 18-65) with bipolar I/II disorder currently experiencing a major depressive episode with a higher probability of inflammatory activity (i.e., meeting one or more of the following inflammatory/metabolic criteria: obesity and dyslipidemia/hypertension, daily cigarette smoking, diabetes mellitus, migraine, inflammatory bowel disease, and/or C-reactive protein level of ⩾5 mg/L) were enrolled in a double-blind, 12-week clinical trial of adjunctive infliximab (5 mg/kg) and saline control, which were administered at weeks 0, 2, and 6. The primary outcome measure for the present secondary analysis was change in the Snaith-Hamilton Pleasure Scale (SHAPS) total score between placebo- and infliximab-treated subjects from baseline to weeks 6 and 12. Plasma concentrations of TNF-α and soluble TNF receptors (sTNFR) 1 and 2 were assessed at weeks 0, 2, 6, and 12. Sixty eligible adults received treatment with infliximab (n=29) or placebo (n=31); 47 subjects completed the study (infliximab: n=21, placebo: n=26). Overall, infliximab-randomized subjects exhibited significantly larger increases in SHAPS total score, denoting greater reductions in anhedonic symptoms, when compared to placebo-randomized subjects (treatment × time interaction effect: χ2=7.15,df=2,p=0.03). Anti-anhedonic efficacy was moderated by baseline plasma levels of TNF-α and sTNFR1, but not by changes in TNF-α or sTNFR1 concentrations. Baseline and changes in sTNFR2 concentrations did not moderate anti-anhedonic efficacy. Infliximab significantly improved a measure of anhedonia relative to placebo in adults with bipolar I/II depression at week 6; intervention efficacy was not sustained 6 weeks after the final infusion.

Is binge eating a cognitive disorder? Results from the International Mood Disorders Collaborative Project.

BACKGROUND: Individuals with binge eating disorder (BED) are differentially affected by attention-deficit/hyperactivity disorder (ADHD), obesity, and substance use disorder. We have investigated to what extent cognitive deficits are relevant to binge eating behavior (BEB). METHODS: Data from the International Mood Disorders Collaborative Project were retrospectively and cross-sectionally analyzed to compare individuals with and without BEB on measures of anhedonia and general cognitive functions (n = 566). BEB was assessed using items from the Mini International Neuropsychiatric Interview Plus 5.0.0 for DSM-IV-TR that correspond with DSM-5-defined diagnostic criteria for BED. Individuals currently prescribed benzodiazepines were excluded from analyses. RESULTS: Individuals with BEB were more likely to exhibit anhedonia (P = .044) and general cognitive (P = .005) symptoms, when compared to those without BEB. We also observed that individuals with BEB were more likely to have specific psychiatric (eg, ADHD) and medical (eg, obesity) disorders (P < .05). CONCLUSIONS: Our results suggest that a central disturbance in cognitive processes may be mechanistically relevant to the cause and treatment of BEB in adults.

Determinants of cognitive function in individuals with type 2 diabetes mellitus: A meta-analysis.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with deficits across multiple cognitive domains; however, the determinants of cognitive impairment in T2DM are not well characterized. We aimed to evaluate body mass index (BMI), glycemic control, and T2DM duration as moderators of cognitive dysfunction in T2DM. METHODS: We conducted a meta-analytic review of the literature reporting data on BMI, hemoglobin A1c (HbA1c), T2DM duration, and validated measures of processing speed (ie, Digit Symbol Substitution Test, Trail Making Test [TMT]-A), verbal learning and memory (ie, Rey Auditory Verbal Learning Test), and working memory/executive function (ie, TMT-B) among individuals with vs without T2DM. RESULTS: Individuals with T2DM demonstrated deficits across multiple cognitive domains (k = 40; n = 4,252 T2DM; n = 22,322 non-T2DM; effect sizes 0.21 to 0.35). Illness duration and BMI did not significantly moderate measures of cognition; however, higher HbA1c levels were significantly associated with deficits in measures of processing speed (R2 values 0.41 to 0.73, P < .01) and working memory/executive function (R2 = 0.62, P < .001). CONCLUSIONS: Adults with T2DM exhibited significant deficits across multiple domains of cognitive function. Additionally, we identified an association between poorer glycemic control and cognitive dysfunction. A clinical translation of our findings relates to the reduction in morbidity by improving glycemic control.

Effects of Antipsychotic Drugs on the Epigenetic Modification of Brain-Derived Neurotrophic Factor Gene Expression in the Hippocampi of Chronic Restraint Stress Rats.

Recent studies have shown that antipsychotic drugs have epigenetic effects. However, the effects of antipsychotic drugs on histone modification remain unclear. Therefore, we investigated the effects of antipsychotic drugs on the epigenetic modification of the BDNF gene in the rat hippocampus. Rats were subjected to chronic restraint stress (6 h/d for 21 d) and then were administered with either olanzapine (2 mg/kg) or haloperidol (1 mg/kg). The levels of histone H3 acetylation and MeCP2 binding at BDNF promoter IV were assessed with chromatin immunoprecipitation assays. The mRNA levels of total BDNF with exon IV, HDAC5, DNMT1, and DNMT3a were assessed with a quantitative RT-PCR procedure. Chronic restraint stress resulted in the downregulation of total and exon IV BDNF mRNA levels and a decrease in histone H3 acetylation and an increase in MeCP2 binding at BDNF promoter IV. Furthermore, there were robust increases in the expression of HDAC5 and DNMTs. Olanzapine administration largely prevented these changes. The administration of haloperidol had no effect. These findings suggest that the antipsychotic drug olanzapine induced histone modification of BDNF gene expression in the hippocampus and that these epigenetic alterations may represent one of the mechanisms underlying the actions of antipsychotic drugs.

Cannabidiol in medical marijuana: Research vistas and potential opportunities.

The high and increasing prevalence of medical marijuana consumption in the general population invites the need for quality evidence regarding its safety and efficacy. Herein, we synthesize extant literature pertaining to the phytocannabinoid cannabidiol (CBD) and its brain effects. The principle phytocannabinoid Δ9-tetrahydrocannabinol (Δ9-THC) and CBD are the major pharmacologically active cannabinoids. The effect of CBD on brain systems as well as on phenomenological measures (e.g. cognitive function) are distinct and in many cases opposite to that of Δ9-THC. Cannabidiol is without euphoriant properties, and exerts antipsychotic, anxiolytic, anti-seizure, as well as anti-inflammatory properties. It is essential to parcellate phytocannabinoids into their constituent moieties as the most abundant cannabinoid have differential effects on physiologic systems in psychopathology measures. Disparate findings and reports related to effects of cannabis consumption reflect differential relative concentration of Δ9-THC and CBD. Existing literature, notwithstanding its deficiencies, provides empirical support for the hypothesis that CBD may exert beneficial effects on brain effector systems/substrates subserving domain-based phenomenology. Interventional studies with purified CBD are warranted with a call to target-engagement proof-of-principle studies using the research domain criteria (RDoC) framework.

Sleep effects of psychological therapies for menopausal symptoms in women with hot flashes and night sweats: A systematic review.

Sleep disturbance is frequently reported by women during the menopausal transition due to various physiological changes and environmental factors. Insomnia is a critical treatment target for its deleterious effects on daytime functioning and quality of life and increased risk of developing a depressive disorder. Due to medication side effects and patient preferences, there is increased interest in the use of psychological treatments that address the myriad of menopausal symptoms, including cognitive-behavioural therapy, clinical hypnosis and mindfulness-based therapies. The objective of this article is to review the effects of psychological treatments for menopausal symptoms on sleep disturbance in peri-/postmenopausal women. We conducted a systematic review of the literature using PubMed and reference lists from inception until May 2023, including 12 studies that evaluated sleep as a secondary outcome. Most studies found that group and self-help (guided and unguided) cognitive-behavioural therapies and clinical hypnosis for menopausal symptoms have positive effects on sleep among women with significant vasomotor symptoms. There was preliminary support for mindfulness-based stress reduction. Future research including more diverse samples and women with sleep disorders is needed. Evaluating the implementation of psychological therapies in clinics where menopausal women seek care is an important next step.

What are patients completing Cognitive Behavioral Insomnia Therapy telling us with their post-treatment Insomnia Severity Index scores?

STUDY OBJECTIVE: Cognitive Behavioral Insomnia Therapy (CBT-I) is the gold standard insomnia treatment and the Insomnia Severity Index (ISI) is a frequently used treatment outcome measure. The ISI has strong psychometric properties and is purported to measure perceived insomnia symptom severity. However, little is known about the factors that drive insomnia severity perception and the psychometric properties of the ISI post-CBT-I. METHODS: Participants were treatment-seeking adults meeting DSM-5 Insomnia Disorder criteria (n = 203, ages 18-77, M = 45.95 years). Participants completed sleep and mood questionnaires, including the ISI, pre- and post-CBT-I. They completed daily Consensus Sleep Diaries each morning throughout two pre-treatment weeks, eight weeks of treatment and two weeks post-treatment. A hierarchical regression analysis examined what predicted post-CBT-I ISI scores and Cronbach's alpha was computed to examine post-treatment reliability of the ISI. RESULTS: The regression analysis revealed that lower post-treatment ISI scores were associated with lower pre-treatment ISI, and greater decreases in fatigue and generalized anxiety symptoms. The model did not significantly improve when pre-treatment sleep effort or changes in sleep diary indices were added. The post-treatment ISI Cronbach's alpha was .88. CONCLUSIONS: Although the ISI has been shown to have sound psychometric properties, clinicians should consider that post CBT-I ISI scores are not related to their sleep improvements. Instead, they seem to be related to whether patients perceive themselves as poor sleepers pre-treatment and whether they felt less tired and anxious after CBT-I. Researchers should consider the impact of factors other than sleep when using the ISI at post-treatment. Patients are telling us that CBT-I should focus on addressing symptoms of fatigue and general anxiety; perhaps CBT-I could be improved further to address these concerns more effectively. SUMMARY: This investigation shows that when individuals are rating their symptom severity after CBT-I, they are also integrating how they felt before treatment and whether they experienced a change in their fatigue or anxiety.

A systematic review of sleep problems in children and adolescents with obsessive compulsive disorder.

There is growing interest in the relationship between obsessive-compulsive disorder (OCD) and sleep problems in youth, including the development of a theoretical model proposing how these disorders maintain each other. The model suggests that OCD symptoms are proposed to interfere with sleep duration (e.g., via increased arousal and delayed bedtime), which compounds OCD symptom severity during the daytime and into the evening, feeding back into the model. Whether the recent influx of research on sleep problems in youth with OCD supports this model is unknown. The primary aim of this systematic review was to characterize sleep problems in youth with OCD and evaluate whether current research supports previous theoretical inferences. Findings across 20 studies revealed a high prevalence of sleep problems among youth with OCD and support a bidirectional relationship. Studies largely did not assess hypothesized relationships proposed by the model; support for the model is therefore preliminary. A secondary aim was to assess the impacts of comorbidity and developmental stage. Findings suggest that in childhood, comorbid anxiety disorders may initially predate sleep problems, but they become mutually maintained over time; the role of comorbid depression appears to increase with age. Limitations, future directions, and clinical implications are discussed.

The role of beliefs about sleep in nightly perceptions of sleep quality across a depression continuum.

BACKGROUND: Poor sleep quality is common in depression, but complaints of poor sleep quality are not necessarily tied to objective sleep, and the construct of sleep quality remains poorly understood. Previous work suggests that beliefs about sleep may influence sleep quality appraisals, as might sleep variability from night to night. OBJECTIVE: We tested whether beliefs about sleep predict daily sleep quality ratings above and beyond nightly variability of actigraphy and diary-assessed sleep over the course of multiple nights. METHODS: Eighty-eight participants aged 18-65 years across a depressive continuum completed sleep diaries and reported their sleep quality and mood each morning; actigraphy was also completed for 67 of those participants. Multilevel models were used to test previous night's total sleep time and sleep efficiency as predictors of self-reported sleep quality (VAS-SQ) and mood (VAS-M), and whether unhelpful beliefs about sleep predicted VAS-SQ and VAS-M above and beyond the sleep variables. RESULTS: Individuals across a depression continuum with greater unhelpful beliefs about sleep reported worse sleep quality and worse mood upon awakening, even when accounting for nightly variation in actigraphy or diary assessed total sleep time and sleep efficiency. CONCLUSIONS: These results suggest that people are influenced by unhelpful sleep beliefs when making judgements about sleep quality and mood, regardless of how well they slept the previous night. Working with these unhelpful sleep beliefs in cognitive behavioral therapy can thus promote better sleep and mood in people across the depressive continuum.

Testing the contiguity of the sleep and fatigue relationship: a daily diary study.

STUDY OBJECTIVES: There is mixed evidence for the relationship between poor sleep and daytime fatigue, and some have suggested that fatigue is simply caused by lack of sleep. Although retrospective measures of insomnia and fatigue tend to correlate, other studies fail to demonstrate a link between objectively disturbed sleep and fatigue. The current study prospectively explored the relationship between sleep and fatigue among those with and without insomnia disorder. METHODS: Participants meeting Research Diagnostic Criteria for insomnia disorder (n = 33) or normal sleepers (n = 32) completed the Consensus Sleep Diary (CSD) and daily fatigue ratings for 2 weeks. Baseline questionnaires evaluated cognitive factors including unhelpful beliefs about sleep and rumination about fatigue. Hierarchical linear modeling tested the within- and between-participant relationships between sleep quality, total sleep time, and daily fatigue ratings. Mediation analyses tested if cognitive factors mediated the relationship between insomnia and fatigue. RESULTS: Self-reported nightly sleep quality significantly predicted subsequent daily fatigue ratings. Total sleep time was a significant predictor of fatigue within, but not between, participants. Unhelpful sleep beliefs and rumination about fatigue mediated the relationship between insomnia and fatigue reporting. CONCLUSIONS: The results suggest that perception of sleep plays an important role in predicting reports of daytime fatigue. These findings could be used in treatment to help shift the focus away from total sleep times, and instead, focus on challenging maladaptive sleep-related cognitions to change fatigue perception.

A Transdiagnostic Self-management Web-Based App for Sleep Disturbance in Adolescents and Young Adults: Feasibility and Acceptability Study.

BACKGROUND: Sleep disturbance and its daytime sequelae, which comprise complex, transdiagnostic sleep problems, are pervasive problems in adolescents and young adults (AYAs) and are associated with negative outcomes. Effective interventions must be both evidence based and individually tailored. Some AYAs prefer self-management and digital approaches. Leveraging these preferences is helpful, given the dearth of AYA treatment providers trained in behavioral sleep medicine. We involved AYAs in the co-design of a behavioral, self-management, transdiagnostic sleep app called DOZE (Delivering Online Zzz's with Empirical Support). OBJECTIVE: This study tests the feasibility and acceptability of DOZE in a community AYA sample aged 15-24 years. The secondary objective is to evaluate sleep and related outcomes in this nonclinical sample. METHODS: Participants used DOZE for 4 weeks (2 periods of 2 weeks). They completed sleep diaries, received feedback on their sleep, set goals in identified target areas, and accessed tips to help them achieve their goals. Measures of acceptability and credibility were completed at baseline and end point. Google Analytics was used to understand the patterns of app use to assess feasibility. Participants completed questionnaires assessing fatigue, sleepiness, chronotype, depression, anxiety, and quality of life at baseline and end point. RESULTS: In total, 83 participants created a DOZE account, and 51 completed the study. During the study, 2659 app sessions took place with an average duration of 3:02 minutes. AYAs tracked most days in period 1 (mean 10.52, SD 4.87) and period 2 (mean 9.81, SD 6.65), with a modal time of 9 AM (within 2 hours of waking). DOZE was appraised as highly acceptable (mode≥4) on the items "easy to use," "easy to understand," "time commitment," and "overall satisfaction" and was rated as credible (mode≥4) at baseline and end point across all items (logic, confident it would work, confident recommending it to a friend, willingness to undergo, and perceived success in treating others). The most common goals set were decreasing schedule variability (34/83, 41% of participants), naps (17/83, 20%), and morning lingering in bed (16/83, 19%). AYAs accessed tips on difficulty winding down (24/83, 29% of participants), being a night owl (17/83, 20%), difficulty getting up (13/83, 16%), and fatigue (13/83, 16%). There were significant improvements in morning lingering in bed (P=.03); total wake time (P=.02); sleep efficiency (P=.002); total sleep time (P=.03); and self-reported insomnia severity (P=.001), anxiety (P=.002), depression (P=.004), and energy (P=.01). CONCLUSIONS: Our results support the feasibility, acceptability, credibility, and preliminary efficacy of DOZE. AYAs are able to set and achieve goals based on tailored feedback on their sleep habits, which is consistent with research suggesting that AYAs prefer autonomy in their health care choices and produce good results when given tools that support their autonomy. TRIAL REGISTRATION: ClinicalTrials.gov NCT03960294; https://clinicaltrials.gov/ct2/show/NCT03960294.

Effects of infliximab on brain neurochemistry of adults with bipolar depression.

OBJECTIVES: To explore the relationship between inflammation and neuronal metabolism in bipolar disorder (BD) by evaluating the neurochemical effects of the tumor necrosis factor-α (TNF-α) antagonist infliximab among individuals with bipolar depression METHODS: This is a post-hoc, exploratory analysis from a 12-week, randomized, double-blind, placebo-controlled trial with infliximab for adults with bipolar depression. We assessed the effects of infliximab on concentration of metabolites in the prefrontal cortex, using proton-magnetic resonance spectroscopy (1H-MRS), as well as its association with clinical outcomes (i.e. depressive symptom severity and cognitive function). RESULTS: Eighteen participants in the placebo and 15 in the infliximab group were included in this analysis. In the pre-specified primary outcome, there were no significant effects of treatment on prefrontal concentrations of N-acetylaspartate (NAA; p = 0.712). In the secondary analyses, there was a significant treatment by time interaction for glutamate (Glx; p = 0.018), indicating that Glx levels decreased in infliximab-treated patients, relative to placebo. Treatment group significantly moderated the association between changes in Glx levels and changes in a neurocognitive test (i.e. Digit Symbol Substitution Test; p = 0.014), indicating that in infliximab-treated participants reductions in Glx were associated with cognitive improvement. CONCLUSIONS: Treatment with infliximab did not affect prefrontal NAA concentration in adults with BD. Exploratory analysis suggested a potential effect of treatment on the glutamate system, a finding that should be confirmed and validated by additional studies.

Leptin mediates improvements in cognitive function following treatment with infliximab in adults with bipolar depression.

A potential role for leptin in the pathophysiology of bipolar disorder (BD) has been proposed. We recently investigated the effects of the tumor necrosis factor-alpha (TNF-α) antagonist infliximab in individuals with bipolar depression. Leptin is known to interact with the TNF-α system. Herein, we aimed to explore infliximab's effects on leptin and its relationship with brain structure and function. Sixty adults with bipolar depression were enrolled in this randomized, double-blind, 12-week clinical trial of adjunctive infliximab (n = 29) and saline control (n = 31), which were administered intravenously at weeks 0, 2, and 6. Plasma concentrations of leptin, TNF-α and soluble TNF receptors (sTNFR) 1 and 2 were assessed at weeks 0, 2, 6, and 12. We observed a significant decrease in leptin levels in infliximab-treated patients, relative to placebo. Infliximab treatment also significantly reduced TNF-α and sTNFR2, but not sTNFR1 levels. Changes in sTNR2 levels at week 6 significantly determined changes in leptin at week 12 in infliximab-, but not placebo-treated participants. Improvements in verbal memory and increases in global cortical volume were associated with reduction in leptin levels in the treatment group. Mediation analysis indicated that cognitive improvement in infliximab-treated patients was mediated by reductions in leptin levels, which in its turn were determined by decreases in sTNR2 levels. In conclusion, infliximab treatment reduced plasma leptin levels in individuals with BD, through modulation of sTNFR2. Decreases in leptin signaling were associated with an increase in global cortical volume and better performance in a verbal memory task.

Machine learning and big data: Implications for disease modeling and therapeutic discovery in psychiatry.

INTRODUCTION: Machine learning capability holds promise to inform disease models, the discovery and development of novel disease modifying therapeutics and prevention strategies in psychiatry. Herein, we provide an introduction on how machine learning/Artificial Intelligence (AI) may instantiate such capabilities, as well as provide rationale for its application to psychiatry in both research and clinical ecosystems. METHODS: Databases PubMed and PsycINFO were searched from 1966 to June 2016 for keywords:Big Data, Machine Learning, Precision Medicine, Artificial Intelligence, Mental Health, Mental Disease, Psychiatry, Data Mining, RDoC, and Research Domain Criteria. Articles selected for review were those that were determined to be aligned with the objective of this particular paper. RESULTS: Results indicate that AI is a viable option to build useful predictors of outcome while offering objective and comparable accuracy metrics, a unique opportunity, particularly in mental health research. The approach has also consistently brought notable insight into disease models through processing the vast amount of already available multi-domain, semi-structured medical data. The opportunity for AI in psychiatry, in addition to disease-model refinement, is in characterizing those at risk, and it is likely also relevant to personalizing and discovering therapeutics. CONCLUSIONS: Machine learning currently provides an opportunity to parse disease models in complex, multi-factorial disease states (e.g. mental disorders) and could possibly inform treatment selection with existing therapies and provide bases for domain-based therapeutic discovery.

Efficacy of Adjunctive Infliximab vs Placebo in the Treatment of Adults With Bipolar I/II Depression: A Randomized Clinical Trial.

Importance: To our knowledge, no study has previously evaluated whether individuals with bipolar depression enriched a priori on the basis of biochemical and/or phenotypic immuno-inflammatory activation would differentially respond to an anti-inflammatory agent for the treatment of depressive symptoms. Objective: To assess the antidepressant efficacy of adjunctive infliximab, a monoclonal antibody targeting tumor necrosis factor, in adults with bipolar I and bipolar II depression and inflammatory conditions. Design, Setting, and Participants: This 12-week, randomized, double-blind, placebo-controlled, parallel-group trial of 60 participants was conducted at 2 outpatient tertiary care sites in Canada and the United States. Eligible adults (aged 18-65 years) met DSM-5-defined criteria for bipolar I or bipolar II depression and exhibited pretreatment biochemical and/or phenotypic evidence of inflammatory activation. Participants were enrolled between October 1, 2015, and April 30, 2018. Data analysis was performed from May 1 through July 31, 2018, using modified intent-to-treat analysis. Interventions: Patients were randomized to receive 3 intravenous infusions of infliximab therapy or placebo at baseline and at weeks 2 and 6 of the 12-week study. Main Outcomes and Measures: The primary efficacy outcome was baseline-to-end point (ie, week-12) change in Montgomery-Asberg Depression Rating Scale (MADRS) total score. History of childhood maltreatment, as assessed by the Childhood Trauma Questionnaire, was used for exploratory analyses as 1 of several secondary outcomes. Results: A total of 60 participants were randomized to infliximab (n = 29 [48%]; mean [SD] age, 45.0 [11.7] years; 20 of 28 female [71%]) or to placebo (n = 31 [52%]; mean [SD] age, 46.8 [10.2] years; 26 of 30 female [87%]) across study sites. Overall baseline-to-end point change in MADRS total score was observed across treatment × time interaction (χ2 = 10.33; P = .04); reduction in symptom severity was not significant at week 12 (relative risk, 1.09; 95% CI, 0.80-1.50; df = 1; P = .60). As part of a secondary analysis, a significant treatment × time × childhood maltreatment interaction was observed in which infliximab-treated individuals with childhood history of physical abuse exhibited greater reductions in MADRS total score (χ2 = 12.20; P = .02) and higher response rates (≥50% reduction in MADRS total score) (χ2 = 4.05; P = .04). Conclusions and Relevance: Infliximab did not significantly reduce depressive symptoms compared with placebo in adults with bipolar depression. Results from secondary analyses identified a subpopulation (ie, those reporting physical and/or sexual abuse) that exhibited a significant reduction in depressive symptoms with infliximab treatment compared with placebo. Trial Registration: ClinicalTrials.gov identifier: NCT02363738.